A low halogenated biphenyl (PCB3) increases CYP1A1 expression and activity via the estrogen receptor beta in the porcine ovary.
Polychlorinated biphenyls (PCBs) have been detected at high levels, up to hundreds of pg/ml, in human ovarian follicle fluid. The effect of PCBs on the ovary and the consequences of exposure are largely unknown. We have previously shown that PCB3 (4-chlorobiphenyl) increases the secretion of estradiol and the activity of cytochrome P450s (CYPs) in ovarian follicle cells. Our goal here is to elucidate the mechanism of CYP induction by this congener. Exposure of porcine follicle cells, a co-culture of theca and granulosa cells, to 6 ng/ml of PCB3 caused an increase in CYP1A1 protein and enzymatic activity, in the same manner as exposure to exogenous 17beta-estradiol. No changes were seen in the protein level of the aryl hydrocarbon receptor (AhR), which mediates the first step in the signaling pathway of CYP1A1 induction. However, a strong reduction was seen in the protein level of estrogen receptor beta (ERbeta), while no effect was seen on ERalpha protein levels. These result suggest that: 1) PCB3 acts as an agonist of ERbeta but not the Ah receptor in the ovarian follicles, 2) PCB3 is not only an efficacious inducer of CYP1A1 expression and activity, but also a substrate for this enzyme. Changes in the expression level of CYP1A1 not only alter the intensity of the activity of PCB3, but also the activity of estrogen in the ovary.
Ptak
A
A
Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Ludewig
G
G
Gregoraszczuk
E Ł
EŁ
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D018920:Coculture Techniques; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006107:Granulosa Cells / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D013552:Swine; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013799:Theca Cells / Q000187:drug effects
D001571:Benzoflavones; D001713:Biphenyl Compounds; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018336:Receptors, Aryl Hydrocarbon; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C011512:alpha-naphthoflavone; D019363:Cytochrome P-450 CYP1A1; C006983:4-chlorobiphenyl